SYMPLIFY Study Clinical Trial Outcomes Data Request

**** On 1st February 2023 NHS Digital merged with NHS England. Where practicable, all references to NHS Digital have been changed to NHS England ***

The University of Oxford and GRAIL Bio UK Ltd, as joint data controllers, are requesting access to pseudonymised record-level data linked against a cohort of individually consented patients recruited to SYMPLIFY, a study designed to assess GRAIL’s Galleri®(Trademarked) multi-cancer early detection (MCED) test in individuals referred with signs and symptoms of cancer.

Note that all members of the team running the trial are based at the Oncology Clinical Trials Office (OCTO) and Primary Care & Vaccine Collaborative Clinical Trials Unit at University of Oxford (UoO). For the sake of consistency, and as UoO is listed as a data controller, when referring to UoO throughout the application, this encompasses the team at OCTO and Primary Care & Vaccine Collaborative Clinical Trials Unit.

Background, Purpose and Rationale behind SYMPLIFY:

SYMPLIFY is a multi-centre, observational study with prospective collection and retrospective analysis of blood samples to evaluate the performance of a multi-cancer early detection test within the NHS in England and Wales. The study enrolled almost 6,000 participants between July and November 2021. Recruitment has now completed on 30 November 2021 with a total of 6,240 participants . Individuals consented are over the age of 18 years, willing and able to give informed consent for participation in the study, and referred to a Rapid Diagnostic Centre for non-specific cancer symptoms or a gynaecological, lung, upper gastrointestinal, or lower gastrointestinal urgent “2-week-wait” (2WW) cancer referral pathway. Participants were consented voluntarily and participants could choose to withdraw their consent at any point during the study.

The Primary objective of the study is to evaluate the performance of a GRAIL’s Galleri® MCED test for the detection of invasive cancer.

The Secondary objectives of the study are to evaluate the:

- Performance and yield of the MCED test by referral pathway(i.e. lung, upper Gastrointestinal (GI), lower GI, gynae, and Rapid Diagnostic Centres (RDC)) and cancer type and stage;

- performance of the MCED test for the identification of cancer signal origin (CSO) by referral pathway.

The Exploratory objectives of the study are to:

- evaluate the completeness of patient data collected from central databases locally within 3 months and by 9 months of enrolment, and centrally monthly from 3 through 12 months post enrolment

- estimate if clinical parameters further optimise the performance of MCED test, resource utilisation, the time to diagnostic resolution. and yield of non-cancer diagnoses by referral pathway at 12 months post enrolment

Following informed consent, participants were registered and assigned a study participant identification number. Approximately 40 mL of whole peripheral blood has been collected from all participants. The blood samples collected from participants have been shipped to a laboratory in the UK for processing to plasma and storage. As an observational study, all medical decision making occurred according to established clinical practice in the relevant clinical pathway. There were no protocol-required diagnostic procedures. The result of any diagnostic procedure(s) will be recorded until the date of diagnostic resolution, with patient level data collected from both participating hospital records and NHS datasets.

Clinical information and demographic data will be collected from all participants via case report forms and NHS data sets.

Follow-up data will be collected at each NHS site within 3 months of enrolment to identify cancer diagnoses and serious disease outcomes, and at a later single time point between 6 and 9 months of enrolment for those without diagnostic resolution at 3 months. Rapid cancer registrations data will be requested for monthly transfer from NCRAS from 3 months through to 11 months of follow-up. At each monthly time-point the data will be locked and stored in separate eCRF. This will allow comparison of the centrally collected monthly rapid cancer registrations data with NHS site collected data.

Full cancer registrations data will be collected at 12 months of follow-up and later at a timepoint when full cancer registrations data is available for the 12 months of follow-up. Patient level electronic health records data collected from primary and secondary will also be requested for the 12 month timepoints to capture cancers diagnosed later and healthcare utilisation following recruitment.

The Trial Management Group (TMG) will be responsible for day to day conduct of the study. The TMG consists of the Chief (Chair) and Lead Investigators, Trials Unit representatives, a University of Oxford representative and representatives from GRAIL. The study will be overseen by the relevant oversight committees of the two trials units involved, taking into account input from the GRAIL Clinical Advisory Group.

GRAIL’s Galleri®(Trademarked) MCED test

A new Multi-Cancer Early Detection (MCED) test has been developed that can detect many types of cancer from a single blood sample. This test is called Galleri®™ and this trial aims to find out whether it is better at discovering cancer early, compared to other tests that the NHS currently uses. GRAIL's Galleri®™ MCED blood test is a qualitative, next-generation sequencing (NGS)-based screening test using cell-free DNA isolated from adult human peripheral whole blood. When a cancer signal is detected, the test can also localise the cancer signal with high accuracy. The test report describes one or two Cancer Signal Origins (CSOs). If the first CSO score is high (≥9.0), then only one CSOs is reported, otherwise the two top CSOs are reported. MCED has 21 possible CSOs: anus; bladder; urothelial tract; bone and soft tissue; breast; cervix; colon, rectum; head and neck; kidney; liver/bile duct; lung; lymphoid lineage; melanocytic lineage; myeloid lineage; neuroendocrine; ovary; pancreas, gallbladder; plasma cell lineage; prostate; stomach, oesophagus; thyroid gland; uterus. It is designed as a screening test and not to confirm a cancer diagnosis. Although the test result of "cancer signal detected" with Cancer Signal Origin may indicate the presence of cancer, further investigations to diagnose cancer are necessary in accordance with professional guidelines. As the test requires clinical validation, no individual results will be returned to the study participants or the clinicians responsible for their care.

Patient and Public Involvement and Engagement (PPI&E)

Ongoing PPI&E is conducted throughout the trial. Historical PPI&E was conducted to develop the participant facing materials and on questionnaires, and including specific questions to PPI groups around the sharing of pseudonymised data with GRAIL, LLC. Ongoing PPI&E includes, for example, PPI&E on new participant facing materials, survey feedback on the participant experience, and questionnaires for follow-up of participants.

In the setting up of the trial, GRAIL has taken seriously, strategies for equity of access and has several plans underway to ensure that under-represented minorities are actively recruited into the trial. Amongst this is the invitation strategy, that will identify and actively send invitations to a greater proportion of individuals from these minorities to take part in the trial. It is hoped that this will positively contribute towards equity of access and inform the provision of cancer services in these areas in the future.

DATA SETS REQUESTED:

> NDRS Linked Hospital Episode Statistics (HES) Admitted Patient Care (APC)

> Emergency Care Data Set (ECDS) - To be released on a monthly basis as planned under version 2 of this agreement.

> NDRS Linked HES Outpatients (OP)

> NDRS Linked Diagnostic Imaging Dataset (DIDS) - Released from August 2022 on monthly basis as planned under version 2 of this agreement.

> NDRS Rapid Cancer Registrations - To be released on a monthly basis as planned under version 2 of this agreement. The study team are requesting the addition of date and cause of death code information for whole cohort. This is required for analysis of key secondary endpoints in the study. Date of death was already requested and disseminated under the Cancer registration data and is now requested under Rapid Cancer Registrations additionally. These additional fields in the Rapid Cancer Registrations do not change the scope or the purpose of the original agreement, they are just a request for an additional flow of data. Death data will also be used for reporting subject disposition in the analysis.

> NDRS Linked Cancer Waiting Times (CWT) (Treatments and Referrals) (CWT) - The study team are requesting to add an additional Cancer Waiting Times referrals from CWT "treatment" table in addition to those from "urgent referrals" table. The change under version 2 of this agreement is required to undertake Health Economic Analysis. No change to dissemination frequency.

> NDRS Cancer Registry - To release NCRD ("gold standard") data on a monthly basis. To expand historic gold standard registration field selection for 1995-2021 and addition of field to allow the trial team to distinguish provisional from finalised gold standard tumours. These changes are required for primary and secondary analysis. Data will be used to characterise the cohort for risk factors (prior cancers), and also assess test performance in a subpopulation of cancer survivors. The Status of Registration is required to enable accurate reporting and filtering of provisional data vs finalised data to internal and external stakeholders, and the interim analysis in the study.

Recruitment for SYMPLIFY occurred between July 2021 to end November 2021. The study team wish to obtain data on participants up to 12 months after last recruitment date, which means the SYMPLIFY team will receive data for the approximate period of 6 months prior to July 2021 to November 2022. Due to the delay in the availability of the final data within the Rapid Cancer registrations and Cancer registration datasets, the study team may not receive their final data drop until around November 2023, however this will only contain data for participants up to November 2022 as per participant consent materials.

JUSTIFICATION FOR DATA SETS REQUESTED AND DATA MINIMISATION

All datasets being requested below are for the SYMPLIFY study enrolled population only. Additionally, only the data fields deemed to be important for analyses have been requested. Provision of data will be limited to 6 months (183 days) prior to the Study Participants’ individual date of consent in the study, up to 12 months after their date of consent. Capturing clinical activity 6 months (183 days) prior to consent date is required to identify the patient cancer history (‘patient pathway’). Due to the nature of the trial patients are, by definition, consented partway through their diagnostic process. Many or even most patients will have relevant clinical events shortly prior to the consent date. The trial team needs to include these events in their analysis in order to answer their primary outcome: to measure the effectiveness of the test as part of the diagnostic process. They will also use these data to assess the diagnostics likely impact on patient level healthcare utilisation and expenditure.

> Cancer Registry and Rapid Registrations - These central NHS datasets will be the sole source for the data required for primary and secondary (exploratory) objectives analyses in the Study. The Cancer Registry provide historical cancer data dating back to 1995. Ascertaining the historic cancer diagnosis background of each study participant is required in order to ascertain the historic cancer diagnosis background of each study participant in case this impacts test results or treatment decisions.

They will be used to identify Primary endpoints, which are:

1. To evaluate the performance of a MCED test for the detection of invasive cancer and the identification of cancer signal origin (CSO).

2. To evaluate the performance of a MCED test by referral pathway (i.e. lung, upper Gastrointestinal (GI), lower GI, gynae, and Rapid Diagnostic Centres (RDC)) and cancer type and stage.

3. To compare the Common Scientific Outline (CSO) predicted by the patient’s GP versus that predicted by MCED.

4. To evaluate the yield with MCED by referral pathway by the number of true positives/number of patients referred within each referral pathway.

5. To evaluate the completeness of patient data collected from central databases by looking at the proportion of completed data fields, according to locally and centrally sourced inputs.

6. To investigate if clinical parameters further optimise the performance of MCED test

7. To evaluate the time to diagnostic resolution by referral pathway.

> Hospital Episode Statistics (HES) Outpatients (OP), Admitted Patient Care (APC) and Emergency Care Data Set (ECDS), Cancer Waiting Times (Referrals) (CWT) and Diagnostic Imaging Dataset (DIDS) - Will be used to identify Secondary endpoints:

1. To estimate resource utilisation by referral pathway by the number of encounters, tests, and referrals required to achieve diagnostic resolution

2. To evaluate the yield of non-cancer diagnoses following referral by the number of patients diagnosed with non-cancer/number of patients referred.

The SYMPLIFY study is funded by an unrestricted educational grant from GRAIL Bio UK Ltd and supported by NHS England, NHS Wales, the National Institute for Health Research (NIHR) and the Oxford NIHR Biomedical Research Centre. NHS England, NHS Wales and the NIHR will not have access to record-level NHS England data, and they do not in any way decide the purpose of the study, how it is run, or the means of data processing, nor have any access to record-level NHS England data. NHS England therefore do not consider them to be a Data Controllers.

GDPR Legal Basis for the Processing of Personal Data:

University of Oxford, as a joint Data Controller, are using Article 6:1(e): Specific task in the ‘public interest’ or task that has a clear basis in law.

GRAIL Bio UK Ltd, as a joint Data Controller, are using Article 6(1)(f) "processing is necessary for the purposes of the legitimate interests pursued by the controller or by a third party except where such interests are overridden by the interests or fundamental rights and freedoms of the data subject which require protection of personal data, in particular where the data subject is a child." Processing personal data is necessary for GRAIL Bio UK Ltd’s legitimate interests which are described in this application. The data to which access is requested are proportionate and necessary to achieve those interests. GRAIL Bio UK Ltd have completed a legitimate interests assessment (LIA) and are satisfied that the interests of the data subjects do not override their legitimate interests; that they would reasonably expect the processing and it would not cause unjustified harm. The data subjects interests and fundamental rights are protected through appropriate minimisation of fields and patient records being processed; protection of the data in a secure environment, and guaranteeing secure destruction at any stage at the request of NHS England or after a defined period on completion of the project. NHS England have compared this LIA against the ICO’s checklist (https://ico.org.uk/for-organisations/guide-to-the-general-data-protection-regulation-gdpr/lawful-basis-for-processing/legitimate-interests/) and are content that all requirements are met.

Additionally (as health data is a special category of Personal Data), both University of Oxford and GRAIL Bio UK Ltd are using Article 9:2(j): Special category data used for “Archiving in the public interest, scientific or historical research or statistical purposes”, with a basis in law.

Organisation Roles and Responsibilities:

• University of Oxford is a joint Data Controller. They are responsible for sponsoring the trial and who also process the data and are responsible for data handling. They will also perform all protocol outlined analyses of NHS England data, and are therefore also the Data Processor for this agreement

• GRAIL Bio UK Ltd is a joint Data Controller. They are responsible for funding the trial and processing and analysing the blood samples. They will not receive any NHS England data outlined in this agreement unless is is aggregated with small number suppression applied as per the HES Analysis guide.

• GRAIL, Limited Liability Company (LLC) are the manufacturers of the MCED test, Galleri®(Trademarked), and has set up the above UK subsidiary, GRAIL Bio UK Ltd.

*** NEW FOR VERSION 5****

GRAIL, LLC have been added under version 5 of this agreement as a data processor. GRAIL, LLC will receive pseudonymised record-level NHS England data from University of Oxford.

• Amazon Web Services, Inc (USA) supply IT infrastructure for GRAIL, LLC and are therefore listed as data processors. They supply support to the system, but do not access data. Therefore, any access to the data held under this agreement would be considered a breach of the agreement. This includes granting of access to the database[s] containing the data. Enrolled participants also consent, as expressly stated in the consent form and participant information sheet, to the transfer of their pseudonymised health data to GRAIL, LLC in the US for purposes permitted by the study participant consent form.

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• Amazon Web Services UK supply IT infrastructure for University of Oxford and are therefore listed as data processors. They supply support to the system, but do not access data. Therefore, any access to the data held under this agreement would be considered a breach of the agreement. This includes granting of access to the database[s] containing the data. AWS UK use only UK data centres and provides a private cloud platform which hosts the CDMS. GRAIL, LLC and GRAIL Bio UK Ltd do not have access to this platform.

COMMERCIAL BENEFIT

GRAIL, LLC is the manufacturer of the MCED test, Galleri®(Trademarked), and has set up a UK subsidiary, GRAIL Bio UK Ltd. In the future, GRAIL Bio UK Ltd may receive commercial benefit (including tangible and intangible benefits, or indirect benefits such as positive publicity) from the successful outcomes of the trial. GRAIL Bio UK Ltd and the NHS have entered into a partnership whereby the Galleri®™ test will be piloted in clinical trials within the NHS in England. If the test is shown to work as intended in these clinical trials, the NHS may purchase the test from GRAIL and make the test routinely available in the future to benefit patients.

In the setting up of the trial, GRAIL has taken seriously, strategies for equity of access and has several plans underway to ensure that under-represented minorities are actively recruited into the trials. Amongst this is the invitation strategy, that will identify and actively send invitations to a greater proportion of individuals from these minorities to take part in the trials. It is hoped that this will positively contribute towards equity of access and inform the provision of cancer services in these areas in the future.

An early interim analysis will be based on data captured within 3 months after enrolment and a late/complete analysis based on data at 12 months after enrolment to account for delayed diagnoses (including the 9-month and 12-month follow-up data). The output from the interim analysis will include a study report summarizing the results of the primary, secondary and first exploratory objective as noted in the Processing Activities section above.

The key exploratory objective for the study is the analysis of the completeness and quality of cancer diagnostic pathway data gathered from central NHS databases as compared to locally collected data. Data-points collected locally within 3 months and by 9 months of enrolment will be compared to data collected centrally monthly from 3 through 12 months post enrolment. The completeness, by capture method, and concordance between methods of each data field will be summarised descriptively in the clinical study reports at both interim and end of study timepoint. This will inform the potential to use central data capture for future large-scale studies in the field, as well as identify areas for improvement in central data linkage.

The outputs of data processing at the end of the study aim to include conference abstracts, reports to NHS England and GRAIL, and submissions of SYMPLIFY findings to peer reviewed journal(s). The publications will not contain the data, only the results of its statistical analysis that will be summarised overall, by cancer site, referral pathway. Health economic analyses aims to examine the number of encounters to diagnosis; number and types of tests for diagnosis; comparisons of resource utilisation observed to modelled resource utilisation based on cancer signal detected and CSO.

All outputs will be aggregated with small number suppressed as per the HES analysis guide or according to the specific data set's suppression guidance.

GRAIL may take the results of the SYMPLIFY study to further refine the algorithm of their MCED test that could add commercial value to their product(s). Results of SYMPLIFY may also inform decisions to fund future cancer research in the NHS and/or future decisions to procure a GRAIL test for use in the NHS.

TARGET DATES

The interim analysis is due to be completed by the end of Quarter 2 in 2022. The final 12-month analysis is expected to be complete by the end of 2023.

This version (v5 - February 2023): Data has not flowed for a long period of time and thus yielded benefits are not reportable at this time but will be included in the next major amendment.

The University of Oxford and GRAIL Bio UK Ltd, as joint data controllers, are requesting access to pseudonymised record-level data linked against a cohort of individually consented patients recruited to SYMPLIFY, a study designed to assess GRAIL’s Galleri®(Trademarked) multi-cancer early detection (MCED) test in individuals referred with signs and symptoms of cancer.

Note that all members of the team running the trial are based at the Oncology Clinical Trials Office (OCTO) and Primary Care & Vaccine Collaborative Clinical Trials Unit at University of Oxford (UoO). For the sake of consistency, and as UoO is listed as a data controller, when referring to UoO throughout the application, this encompasses the team at OCTO and Primary Care & Vaccine Collaborative Clinical Trials Unit.

Background, Purpose and Rationale behind SYMPLIFY:

SYMPLIFY is a multi-centre, observational study with prospective collection and retrospective analysis of blood samples to evaluate the performance of a multi-cancer early detection test within the NHS in England and Wales. The study enrolled almost 6,000 participants between July and November 2021. Recruitment has now completed on 30 November 2021 with a total of 6,240 participants . Individuals consented are over the age of 18 years, willing and able to give informed consent for participation in the study, and referred to a Rapid Diagnostic Centre for non-specific cancer symptoms or a gynaecological, lung, upper gastrointestinal, or lower gastrointestinal urgent “2-week-wait” (2WW) cancer referral pathway. Participants were consented voluntarily and participants could choose to withdraw their consent at any point during the study.

The Primary objective of the study is to evaluate the performance of a GRAIL’s Galleri® MCED test for the detection of invasive cancer.

The Secondary objectives of the study are to evaluate the:

- Performance and yield of the MCED test by referral pathway(i.e. lung, upper Gastrointestinal (GI), lower GI, gynae, and Rapid Diagnostic Centres (RDC)) and cancer type and stage;

- performance of the MCED test for the identification of cancer signal origin (CSO) by referral pathway.

The Exploratory objectives of the study are to:

- evaluate the completeness of patient data collected from central databases locally within 3 months and by 9 months of enrolment, and centrally monthly from 3 through 12 months post enrolment

- estimate if clinical parameters further optimise the performance of MCED test, resource utilisation, the time to diagnostic resolution. and yield of non-cancer diagnoses by referral pathway at 12 months post enrolment

Following informed consent, participants were registered and assigned a study participant identification number. Approximately 40 mL of whole peripheral blood has been collected from all participants. The blood samples collected from participants have been shipped to a laboratory in the UK for processing to plasma and storage. As an observational study, all medical decision making occurred according to established clinical practice in the relevant clinical pathway. There were no protocol-required diagnostic procedures. The result of any diagnostic procedure(s) will be recorded until the date of diagnostic resolution, with patient level data collected from both participating hospital records and NHS datasets.

Clinical information and demographic data will be collected from all participants via case report forms and NHS data sets.

Follow-up data will be collected at each NHS site within 3 months of enrolment to identify cancer diagnoses and serious disease outcomes, and at a later single time point between 6 and 9 months of enrolment for those without diagnostic resolution at 3 months. Rapid cancer registrations data will be requested for monthly transfer from NCRAS from 3 months through to 11 months of follow-up. At each monthly time-point the data will be locked and stored in separate eCRF. This will allow comparison of the centrally collected monthly rapid cancer registrations data with NHS site collected data.

Full cancer registrations data will be collected at 12 months of follow-up and later at a timepoint when full cancer registrations data is available for the 12 months of follow-up. Patient level electronic health records data collected from primary and secondary will also be requested for the 12 month timepoints to capture cancers diagnosed later and healthcare utilisation following recruitment.

The Trial Management Group (TMG) will be responsible for day to day conduct of the study. The TMG consists of the Chief (Chair) and Lead Investigators, Trials Unit representatives, a University of Oxford representative and representatives from GRAIL. The study will be overseen by the relevant oversight committees of the two trials units involved, taking into account input from the GRAIL Clinical Advisory Group.

GRAIL’s Galleri®(Trademarked) MCED test

A new Multi-Cancer Early Detection (MCED) test has been developed that can detect many types of cancer from a single blood sample. This test is called Galleri®™ and this trial aims to find out whether it is better at discovering cancer early, compared to other tests that the NHS currently uses. GRAIL's Galleri®™ MCED blood test is a qualitative, next-generation sequencing (NGS)-based screening test using cell-free DNA isolated from adult human peripheral whole blood. When a cancer signal is detected, the test can also localise the cancer signal with high accuracy. The test report describes one or two Cancer Signal Origins (CSOs). If the first CSO score is high (≥9.0), then only one CSOs is reported, otherwise the two top CSOs are reported. MCED has 21 possible CSOs: anus; bladder; urothelial tract; bone and soft tissue; breast; cervix; colon, rectum; head and neck; kidney; liver/bile duct; lung; lymphoid lineage; melanocytic lineage; myeloid lineage; neuroendocrine; ovary; pancreas, gallbladder; plasma cell lineage; prostate; stomach, oesophagus; thyroid gland; uterus. It is designed as a screening test and not to confirm a cancer diagnosis. Although the test result of "cancer signal detected" with Cancer Signal Origin may indicate the presence of cancer, further investigations to diagnose cancer are necessary in accordance with professional guidelines. As the test requires clinical validation, no individual results will be returned to the study participants or the clinicians responsible for their care.

Patient and Public Involvement and Engagement (PPI&E)

Ongoing PPI&E is conducted throughout the trial. Historical PPI&E was conducted to develop the participant facing materials and on questionnaires, and including specific questions to PPI groups around the sharing of pseudonymised data with GRAIL, LLC. Ongoing PPI&E includes, for example, PPI&E on new participant facing materials, survey feedback on the participant experience, and questionnaires for follow-up of participants.

In the setting up of the trial, GRAIL has taken seriously, strategies for equity of access and has several plans underway to ensure that under-represented minorities are actively recruited into the trial. Amongst this is the invitation strategy, that will identify and actively send invitations to a greater proportion of individuals from these minorities to take part in the trial. It is hoped that this will positively contribute towards equity of access and inform the provision of cancer services in these areas in the future.

DATA SETS REQUESTED:

> NDRS Linked Hospital Episode Statistics (HES) Admitted Patient Care (APC)

> Emergency Care Data Set (ECDS) - To be released on a monthly basis as planned under version 2 of this agreement.

> NDRS Linked HES Outpatients (OP)

> NDRS Linked Diagnostic Imaging Dataset (DIDS) - Released from August 2022 on monthly basis as planned under version 2 of this agreement.

> NDRS Rapid Cancer Registrations - To be released on a monthly basis as planned under version 2 of this agreement. The study team are requesting the addition of date and cause of death code information for whole cohort. This is required for analysis of key secondary endpoints in the study. Date of death was already requested and disseminated under the Cancer registration data and is now requested under Rapid Cancer Registrations additionally. These additional fields in the Rapid Cancer Registrations do not change the scope or the purpose of the original agreement, they are just a request for an additional flow of data. Death data will also be used for reporting subject disposition in the analysis.

> NDRS Linked Cancer Waiting Times (CWT) (Treatments and Referrals) (CWT) - The study team are requesting to add an additional Cancer Waiting Times referrals from CWT "treatment" table in addition to those from "urgent referrals" table. The change under version 2 of this agreement is required to undertake Health Economic Analysis. No change to dissemination frequency.

> NDRS Cancer Registry - To release NCRD ("gold standard") data on a monthly basis. To expand historic gold standard registration field selection for 1995-2021 and addition of field to allow the trial team to distinguish provisional from finalised gold standard tumours. These changes are required for primary and secondary analysis. Data will be used to characterise the cohort for risk factors (prior cancers), and also assess test performance in a subpopulation of cancer survivors. The Status of Registration is required to enable accurate reporting and filtering of provisional data vs finalised data to internal and external stakeholders, and the interim analysis in the study.

Recruitment for SYMPLIFY occurred between July 2021 to end November 2021. The study team wish to obtain data on participants up to 12 months after last recruitment date, which means the SYMPLIFY team will receive data for the period of July 2021 to November 2022. Due to the delay in the availability of the final data within the Rapid Cancer registrations and Cancer registration datasets, the study team may not receive their final data drop until around November 2023, however this will only contain data for participants up to November 2022 as per participant consent materials.

JUSTIFICATION FOR DATA SETS REQUESTED AND DATA MINIMISATION

**** Amendment to Version 3 of agreement ****

All datasets being requested below are for the SYMPLIFY study enrolled population only. Additionally, only the data fields deemed to be important for analyses have been requested. Provision of data will be limited to 6 months (183 days) prior to the Study Participants’ individual date of consent in the study, up to 12 months after their date of consent. Capturing clinical activity 6 months (183 days) prior to consent date is required to identify the patient cancer history (‘patient pathway’). Due to the nature of the trial patients are, by definition, consented partway through their diagnostic process. Many or even most patients will have relevant clinical events shortly prior to the consent date. The trial team needs to include these events in their analysis in order to answer their primary outcome: to measure the effectiveness of the test as part of the diagnostic process. They will also use these data to assess the diagnostics likely impact on patient level healthcare utilisation and expenditure.

> Cancer Registry and Rapid Registrations - These central NHS datasets will be the sole source for the data required for primary and secondary (exploratory) objectives analyses in the Study. The Cancer Registry provide historical cancer data dating back to 1995. Ascertaining the historic cancer diagnosis background of each study participant is required in order to ascertain the historic cancer diagnosis background of each study participant in case this impacts test results or treatment decisions.

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They will be used to identify Primary endpoints, which are:

1. To evaluate the performance of a MCED test for the detection of invasive cancer and the identification of cancer signal origin (CSO).

2. To evaluate the performance of a MCED test by referral pathway (i.e. lung, upper Gastrointestinal (GI), lower GI, gynae, and Rapid Diagnostic Centres (RDC)) and cancer type and stage.

3. To compare the Common Scientific Outline (CSO) predicted by the patient’s GP versus that predicted by MCED.

4. To evaluate the yield with MCED by referral pathway by the number of true positives/number of patients referred within each referral pathway.

5. To evaluate the completeness of patient data collected from central databases by looking at the proportion of completed data fields, according to locally and centrally sourced inputs.

6. To investigate if clinical parameters further optimise the performance of MCED test

7. To evaluate the time to diagnostic resolution by referral pathway.

> Hospital Episode Statistics (HES) Outpatients (OP), Admitted Patient Care (APC) and Emergency Care Data Set (ECDS), Cancer Waiting Times (Referrals) (CWT) and Diagnostic Imaging Dataset (DIDS) - Will be used to identify Secondary endpoints:

1. To estimate resource utilisation by referral pathway by the number of encounters, tests, and referrals required to achieve diagnostic resolution

2. To evaluate the yield of non-cancer diagnoses following referral by the number of patients diagnosed with non-cancer/number of patients referred.

The SYMPLIFY study is funded by an unrestricted educational grant from GRAIL Bio UK Ltd and supported by NHS England, NHS Wales, the National Institute for Health Research (NIHR) and the Oxford NIHR Biomedical Research Centre. NHS England, NHS Wales and the NIHR will not have access to record-level NHS Digital data, and they do not in any way decide the purpose of the study, how it is run, or the means of data processing, nor have any access to record-level NHS Digital data. NHS Digital therefore do not consider them to be a Data Controllers.

GDPR Legal Basis for the Processing of Personal Data:

University of Oxford, as joint Data Controller (and Lead), are using Article 6:1(e): Specific task in the ‘public interest’ or task that has a clear basis in law.

GRAIL Bio UK Ltd, as a joint Data Controller, are using Article 6(1)(f) "processing is necessary for the purposes of the legitimate interests pursued by the controller or by a third party except where such interests are overridden by the interests or fundamental rights and freedoms of the data subject which require protection of personal data, in particular where the data subject is a child." Processing personal data is necessary for GRAIL Bio UK Ltd’s legitimate interests which are described in this application. The data to which access is requested are proportionate and necessary to achieve those interests. GRAIL Bio UK Ltd have completed a legitimate interests assessment (LIA) and are satisfied that the interests of the data subjects do not override their legitimate interests; that they would reasonably expect the processing and it would not cause unjustified harm. The data subjects interests and fundamental rights are protected through appropriate minimisation of fields and patient records being processed; protection of the data in a secure environment, and guaranteeing secure destruction at any stage at the request of NHS Digital or after a defined period on completion of the project. NHS Digital have compared this LIA against the ICO’s checklist (https://ico.org.uk/for-organisations/guide-to-the-general-data-protection-regulation-gdpr/lawful-basis-for-processing/legitimate-interests/) and are content that all requirements are met.

Additionally (as health data is a special category of Personal Data), both University of Oxford and GRAIL Bio UK Ltd are using Article 9:2(j): Special category data used for “Archiving in the public interest, scientific or historical research or statistical purposes”, with a basis in law.

Organisation Roles and Responsibilities:

• University of Oxford is the lead Data Controller. They are responsible for sponsoring the trial and who also process the data and are responsible for data handling. They will also perform all protocol outlined analyses of NHS Digital data, and are therefore also the Data Processor for this agreement

• GRAIL Bio UK Ltd are the joint Data Controller. They are responsible for funding the trial and processing and analysing the blood samples. They will not receive any NHS Digital data outlined in this agreement unless is is aggregated with small number suppression applied as per the HES Analysis guide.

• GRAIL, Limited Liability Company (LLC). are the manufacturers of the MCED test, Galleri®(Trademarked), and has set up the above UK subsidiary, GRAIL Bio UK Ltd. When approval is in place and this agreement has been updated through the NHS Digital assurance process, GRAIL, LLC will be added as a data processor. At that time, GRAIL, LLC will be receiving pseudonymised record-level NHS Digital data from University of Oxford *** Under this version (v2) and version 1 of this agreement, the pseudonymised record-level data will not yet be transferred outside of the UK. ***

In the future, GRAIL Bio UK Ltd may receive commercial benefit (including intangible or indirect commercial benefits such as positive publicity) from the successful outcomes of the trial. GRAIL Bio UK Ltd and the NHS have entered into a partnership whereby the Galleri®™ test will be piloted in clinical trials within the NHS in England. If the test is shown to work as intended in these clinical trials, the NHS may purchase the test from GRAIL and make the test routinely available in the future to benefit patient.

An early interim analysis will be based on data captured within 3 months after enrolment and a late/complete analysis based on data at 12 months after enrolment to account for delayed diagnoses (including the 9-month and 12-month follow-up data). The output from the interim analysis will include a study report summarizing the results of the primary, secondary and first exploratory objective as noted in the Processing Activities section above.

The key exploratory objective for the study is the analysis of the completeness and quality of cancer diagnostic pathway data gathered from central NHS databases as compared to locally collected data. Datapoints collected locally within 3 months and by 9 months of enrolment will be compared to data collected centrally monthly from 3 through 12 months post enrolment. The completeness, by capture method, and concordance between methods of each data field will be summarised descriptively in the clinical study reports at both interim and end of study timepoint. This will inform the potential to use central data capture for future large-scale studies in the field, as well as identify areas for improvement in central data linkage.

The outputs of data processing at the end of the study aim to include conference abstracts, reports to NHS England and GRAIL, and submissions of SYMPLIFY findings to peer reviewed journal(s). The publications will not contain the data, only the results of its statistical analysis that will be summarised overall, by cancer site, referral pathway. Health economic analyses aims to examine the number of encounters to diagnosis; number and types of tests for diagnosis; comparisons of resource utilisation observed to modelled resource utilisation based on cancer signal detected and CSO.

All outputs will be aggregated with small number suppressed as per the HES analysis guide or according to the specific data set's suppression guidance.

GRAIL may take the results of the SYMPLIFY study to further refine the algorithm of their MCED test that could add commercial value to their product(s). Results of SYMPLIFY may also inform decisions to fund future cancer research in the NHS and/or future decisions to procure a GRAIL test for use in the NHS.

TARGET DATES

The interim analysis is due to be completed by the end of Quarter 2 in 2022. The final 12-month analysis is expected to be complete by the end of 2023.

This version (v2 - October 2022) is a minor amendment to the data specification. Yielded benefits are not reportable at this time but will be included in the next major amendment.

The University of Oxford and GRAIL Bio UK Ltd, as joint data controllers, are requesting access to pseudonymised record-level data linked against a cohort of individually consented patients recruited to SYMPLIFY, a study designed to assess GRAIL’s Galleri®(Trademarked) multi-cancer early detection (MCED) test in individuals referred with signs and symptoms of cancer.

Note that all members of the team running the trial are based at the Oncology Clinical Trials Office (OCTO) and Primary Care & Vaccine Collaborative Clinical Trials Unit at University of Oxford (UoO). For the sake of consistency, and as UoO is listed as a data controller, when referring to UoO throughout the application, this encompasses the team at OCTO and Primary Care & Vaccine Collaborative Clinical Trials Unit.

Background, Purpose and Rationale behind SYMPLIFY:

SYMPLIFY is a multi-centre, observational study with prospective collection and retrospective analysis of blood samples to evaluate the performance of a multi-cancer early detection test within the NHS in England and Wales. The study enrolled almost 6,000 participants between July and November 2021. Recruitment has now completed on 30 November 2021 with a total of 6,240 participants . Individuals consented are over the age of 18 years, willing and able to give informed consent for participation in the study, and referred to a Rapid Diagnostic Centre for non-specific cancer symptoms or a gynaecological, lung, upper gastrointestinal, or lower gastrointestinal urgent “2-week-wait” (2WW) cancer referral pathway. Participants were consented voluntarily and participants could choose to withdraw their consent at any point during the study.

The Primary objective of the study is to evaluate the performance of a GRAIL’s Galleri® MCED test for the detection of invasive cancer.

The Secondary objectives of the study are to evaluate the:

- Performance and yield of the MCED test by referral pathway(i.e. lung, upper Gastrointestinal (GI), lower GI, gynae, and Rapid Diagnostic Centres (RDC)) and cancer type and stage;

- performance of the MCED test for the identification of cancer signal origin (CSO) by referral pathway.

The Exploratory objectives of the study are to:

- evaluate the completeness of patient data collected from central databases locally within 3 months and by 9 months of enrolment, and centrally monthly from 3 through 12 months post enrolment

- estimate if clinical parameters further optimise the performance of MCED test, resource utilisation, the time to diagnostic resolution. and yield of non-cancer diagnoses by referral pathway at 12 months post enrolment

Following informed consent, participants were registered and assigned a study participant identification number. Approximately 40 mL of whole peripheral blood has been collected from all participants. The blood samples collected from participants have been shipped to a laboratory in the UK for processing to plasma and storage. As an observational study, all medical decision making occurred according to established clinical practice in the relevant clinical pathway. There were no protocol-required diagnostic procedures. The result of any diagnostic procedure(s) will be recorded until the date of diagnostic resolution, with patient level data collected from both participating hospital records and NHS datasets.

Clinical information and demographic data will be collected from all participants via case report forms and NHS data sets.

Follow-up data will be collected at each NHS site within 3 months of enrolment to identify cancer diagnoses and serious disease outcomes, and at a later single time point between 6 and 9 months of enrolment for those without diagnostic resolution at 3 months. Rapid cancer registrations data will be requested for monthly transfer from NCRAS from 3 months through to 11 months of follow-up. At each monthly time-point the data will be locked and stored in separate eCRF. This will allow comparison of the centrally collected monthly rapid cancer registrations data with NHS site collected data.

Full cancer registrations data will be collected at 12 months of follow-up and later at a timepoint when full cancer registrations data is available for the 12 months of follow-up. Patient level electronic health records data collected from primary and secondary will also be requested for the 12 month timepoints to capture cancers diagnosed later and healthcare utilisation following recruitment.

The Trial Management Group (TMG) will be responsible for day to day conduct of the study. The TMG consists of the Chief (Chair) and Lead Investigators, Trials Unit representatives, a University of Oxford representative and representatives from GRAIL. The study will be overseen by the relevant oversight committees of the two trials units involved, taking into account input from the GRAIL Clinical Advisory Group.

GRAIL’s Galleri®(Trademarked) MCED test

A new Multi-Cancer Early Detection (MCED) test has been developed that can detect many types of cancer from a single blood sample. This test is called Galleri®™ and this trial aims to find out whether it is better at discovering cancer early, compared to other tests that the NHS currently uses. GRAIL's Galleri®™ MCED blood test is a qualitative, next-generation sequencing (NGS)-based screening test using cell-free DNA isolated from adult human peripheral whole blood. When a cancer signal is detected, the test can also localise the cancer signal with high accuracy. The test report describes one or two Cancer Signal Origins (CSOs). If the first CSO score is high (≥9.0), then only one CSOs is reported, otherwise the two top CSOs are reported. MCED has 21 possible CSOs: anus; bladder; urothelial tract; bone and soft tissue; breast; cervix; colon, rectum; head and neck; kidney; liver/bile duct; lung; lymphoid lineage; melanocytic lineage; myeloid lineage; neuroendocrine; ovary; pancreas, gallbladder; plasma cell lineage; prostate; stomach, oesophagus; thyroid gland; uterus. It is designed as a screening test and not to confirm a cancer diagnosis. Although the test result of "cancer signal detected" with Cancer Signal Origin may indicate the presence of cancer, further investigations to diagnose cancer are necessary in accordance with professional guidelines. As the test requires clinical validation, no individual results will be returned to the study participants or the clinicians responsible for their care.

Patient and Public Involvement and Engagement (PPI&E)

Ongoing PPI&E is conducted throughout the trial. Historical PPI&E was conducted to develop the participant facing materials and on questionnaires, and including specific questions to PPI groups around the sharing of pseudonymised data with GRAIL, LLC. Ongoing PPI&E includes, for example, PPI&E on new participant facing materials, survey feedback on the participant experience, and questionnaires for follow-up of participants.

In the setting up of the trial, GRAIL has taken seriously, strategies for equity of access and has several plans underway to ensure that under-represented minorities are actively recruited into the trial. Amongst this is the invitation strategy, that will identify and actively send invitations to a greater proportion of individuals from these minorities to take part in the trial. It is hoped that this will positively contribute towards equity of access and inform the provision of cancer services in these areas in the future.

DATA SETS REQUESTED:

> Rapid Registrations Cancer Data Set

> Cancer Registry

> Hospital Episode Statistics (HES) Admitted Patient Care (APC)

> Emergency Care Data Set (ECDS)

> HES Outpatients (OP)

> Cancer Waiting Times (Referral data for patients not diagnosed (and therefore not treated)) (CWT)

> Diagnostic Imaging Dataset (DIDS)

> HES Admitted Patient Care (APC)

> HES Outpatients (OP)

> Emergency Care Dataset (ECDS) - To be released on a monthly basis as planned under version 2 of this agreement.

> Diagnostic Imaging Dataset (DIDS) - Released from August 2022 on monthly basis as planned under version 2 of this agreement.

> Rapid Cancer Registrations Dataset - To be released on a monthly basis as planned under version 2 of this agreement. The study team are requesting the addition of date and cause of death code information for whole cohort. This is required for analysis of key secondary endpoints in the study. Date of death was already requested and disseminated under the Cancer registration data and is now requested under Rapid Cancer Registrations additionally. These additional fields in the Rapid Cancer Registrations do not change the scope or the purpose of the original agreement, they are just a request for an additional flow of data. Death data will also be used for reporting subject disposition in the analysis.

> Cancer Waiting Times (CWT) - The study team are requesting to add an additional Cancer Waiting Times referrals from CWT "treatment" table in addition to those from "urgent referrals" table. This change under version 2 of this agreement is required to undertake Health Economic Analysis. No change to dissemination frequency.

> Cancer Registration Data - To release NCRD ("gold standard") data on a monthly basis. To expand historic gold standard registration field selection for 1995-2021 and addition of field to allow the trial team to distinguish provisional from finalised gold standard tumours. These changes are required for primary and secondary analysis. Data will be used to characterise the cohort for risk factors (prior cancers), and also assess test performance in a subpopulation of cancer survivors. The Status of Registration is required to enable accurate reporting and filtering of provisional data vs finalised data to internal and external stakeholders, and the interim analysis in the study.

Recruitment for SYMPLIFY occurred between July 2021 to end November 2021. The study team wish to obtain data on participants up to 12 months after last recruitment date, which means the SYMPLIFY team will receive data for the period of July 2021 to November 2022. Due to the delay in the availability of the final data within the Rapid Cancer registrations and Cancer registration datasets, the study team may not receive their final data drop until around November 2023, however this will only contain data for participants up to November 2022 as per participant consent materials.

JUSTIFICATION FOR DATA SETS REQUESTED AND DATA MINIMISATION

**** Amendment to Version 3 of agreement ****

All datasets being requested below are for the SYMPLIFY study enrolled population only. Additionally, only the data fields deemed to be important for analyses have been requested. Provision of data will be limited to 6 months (183 days) prior to the Study Participants’ individual date of consent in the study, up to 12 months after their date of consent. Capturing clinical activity 6 months (183 days) prior to consent date is required to identify the patient cancer history (‘patient pathway’). Due to the nature of the trial patients are, by definition, consented partway through their diagnostic process. Many or even most patients will have relevant clinical events shortly prior to the consent date. The trial team needs to include these events in their analysis in order to answer their primary outcome: to measure the effectiveness of the test as part of the diagnostic process. They will also use these data to assess the diagnostics likely impact on patient level healthcare utilisation and expenditure.

> Cancer Registry and Rapid Registrations - These central NHS datasets will be the sole source for the data required for primary and secondary (exploratory) objectives analyses in the Study. The Cancer Registry provide historical cancer data dating back to 1995. Ascertaining the historic cancer diagnosis background of each study participant is required in order to ascertain the historic cancer diagnosis background of each study participant in case this impacts test results or treatment decisions.

*****************************************************

They will be used to identify Primary endpoints, which are:

1. To evaluate the performance of a MCED test for the detection of invasive cancer and the identification of cancer signal origin (CSO).

2. To evaluate the performance of a MCED test by referral pathway (i.e. lung, upper Gastrointestinal (GI), lower GI, gynae, and Rapid Diagnostic Centres (RDC)) and cancer type and stage.

3. To compare the Common Scientific Outline (CSO) predicted by the patient’s GP versus that predicted by MCED.

4. To evaluate the yield with MCED by referral pathway by the number of true positives/number of patients referred within each referral pathway.

5. To evaluate the completeness of patient data collected from central databases by looking at the proportion of completed data fields, according to locally and centrally sourced inputs.

6. To investigate if clinical parameters further optimise the performance of MCED test

7. To evaluate the time to diagnostic resolution by referral pathway.

> Hospital Episode Statistics (HES) Outpatients (OP), Admitted Patient Care (APC) and Emergency Care Data Set (ECDS), Cancer Waiting Times (Referrals) (CWT) and Diagnostic Imaging Dataset (DIDS) - Will be used to identify Secondary endpoints:

1. To estimate resource utilisation by referral pathway by the number of encounters, tests, and referrals required to achieve diagnostic resolution

2. To evaluate the yield of non-cancer diagnoses following referral by the number of patients diagnosed with non-cancer/number of patients referred.

The SYMPLIFY study is funded by an unrestricted educational grant from GRAIL Bio UK Ltd and supported by NHS England, NHS Wales, the National Institute for Health Research (NIHR) and the Oxford NIHR Biomedical Research Centre. NHS England, NHS Wales and the NIHR will not have access to record-level NHS Digital data, and they do not in any way decide the purpose of the study, how it is run, or the means of data processing, nor have any access to record-level NHS Digital data. NHS Digital therefore do not consider them to be a Data Controllers.

GDPR Legal Basis for the Processing of Personal Data:

University of Oxford, as joint Data Controller (and Lead), are using Article 6:1(e): Specific task in the ‘public interest’ or task that has a clear basis in law.

GRAIL Bio UK Ltd, as a joint Data Controller, are using Article 6(1)(f) "processing is necessary for the purposes of the legitimate interests pursued by the controller or by a third party except where such interests are overridden by the interests or fundamental rights and freedoms of the data subject which require protection of personal data, in particular where the data subject is a child." Processing personal data is necessary for GRAIL Bio UK Ltd’s legitimate interests which are described in this application. The data to which access is requested are proportionate and necessary to achieve those interests. GRAIL Bio UK Ltd have completed a legitimate interests assessment (LIA) and are satisfied that the interests of the data subjects do not override their legitimate interests; that they would reasonably expect the processing and it would not cause unjustified harm. The data subjects interests and fundamental rights are protected through appropriate minimisation of fields and patient records being processed; protection of the data in a secure environment, and guaranteeing secure destruction at any stage at the request of NHS Digital or after a defined period on completion of the project. NHS Digital have compared this LIA against the ICO’s checklist (https://ico.org.uk/for-organisations/guide-to-the-general-data-protection-regulation-gdpr/lawful-basis-for-processing/legitimate-interests/) and are content that all requirements are met.

Additionally (as health data is a special category of Personal Data), both University of Oxford and GRAIL Bio UK Ltd are using Article 9:2(j): Special category data used for “Archiving in the public interest, scientific or historical research or statistical purposes”, with a basis in law.

Organisation Roles and Responsibilities:

• University of Oxford is the lead Data Controller. They are responsible for sponsoring the trial and who also process the data and are responsible for data handling. They will also perform all protocol outlined analyses of NHS Digital data, and are therefore also the Data Processor for this agreement

• GRAIL Bio UK Ltd are the joint Data Controller. They are responsible for funding the trial and processing and analysing the blood samples. They will not receive any NHS Digital data outlined in this agreement unless is is aggregated with small number suppression applied as per the HES Analysis guide.

• GRAIL, Limited Liability Company (LLC). are the manufacturers of the MCED test, Galleri®(Trademarked), and has set up the above UK subsidiary, GRAIL Bio UK Ltd. When approval is in place and this agreement has been updated through the NHS Digital assurance process, GRAIL, LLC will be added as a data processor. At that time, GRAIL, LLC will be receiving pseudonymised record-level NHS Digital data from University of Oxford *** Under this version (v2) and version 1 of this agreement, the pseudonymised record-level data will not yet be transferred outside of the UK. ***

In the future, GRAIL Bio UK Ltd may receive commercial benefit (including intangible or indirect commercial benefits such as positive publicity) from the successful outcomes of the trial. GRAIL Bio UK Ltd and the NHS have entered into a partnership whereby the Galleri®™ test will be piloted in clinical trials within the NHS in England. If the test is shown to work as intended in these clinical trials, the NHS may purchase the test from GRAIL and make the test routinely available in the future to benefit patient.

An early interim analysis will be based on data captured within 3 months after enrolment and a late/complete analysis based on data at 12 months after enrolment to account for delayed diagnoses (including the 9-month and 12-month follow-up data). The output from the interim analysis will include a study report summarizing the results of the primary, secondary and first exploratory objective as noted in the Processing Activities section above.

The key exploratory objective for the study is the analysis of the completeness and quality of cancer diagnostic pathway data gathered from central NHS databases as compared to locally collected data. Datapoints collected locally within 3 months and by 9 months of enrolment will be compared to data collected centrally monthly from 3 through 12 months post enrolment. The completeness, by capture method, and concordance between methods of each data field will be summarised descriptively in the clinical study reports at both interim and end of study timepoint. This will inform the potential to use central data capture for future large-scale studies in the field, as well as identify areas for improvement in central data linkage.

The outputs of data processing at the end of the study aim to include conference abstracts, reports to NHS England and GRAIL, and submissions of SYMPLIFY findings to peer reviewed journal(s). The publications will not contain the data, only the results of its statistical analysis that will be summarised overall, by cancer site, referral pathway. Health economic analyses aims to examine the number of encounters to diagnosis; number and types of tests for diagnosis; comparisons of resource utilisation observed to modelled resource utilisation based on cancer signal detected and CSO.

All outputs will be aggregated with small number suppressed as per the HES analysis guide or according to the specific data set's suppression guidance.

GRAIL may take the results of the SYMPLIFY study to further refine the algorithm of their MCED test that could add commercial value to their product(s). Results of SYMPLIFY may also inform decisions to fund future cancer research in the NHS and/or future decisions to procure a GRAIL test for use in the NHS.

TARGET DATES

The interim analysis is due to be completed by the end of Quarter 2 in 2022. The final 12-month analysis is expected to be complete by the end of 2023.

This version (v2 - October 2022) is a minor amendment to the data specification. Yielded benefits are not reportable at this time but will be included in the next major amendment.

The University of Oxford and GRAIL Bio UK Ltd, as joint data controllers, are requesting access to pseudonymised record-level data linked against a cohort of individually consented patients recruited to SYMPLIFY, a study designed to assess GRAIL’s Galleri®(Trademarked) multi-cancer early detection (MCED) test in individuals referred with signs and symptoms of cancer.

Note that all members of the team running the trial are based at the Oncology Clinical Trials Office (OCTO) and Primary Care & Vaccine Collaborative Clinical Trials Unit at University of Oxford (UoO). For the sake of consistency, and as UoO is listed as a data controller, when referring to UoO throughout the application, this encompasses the team at OCTO and Primary Care & Vaccine Collaborative Clinical Trials Unit.

Background, Purpose and Rationale behind SYMPLIFY:

SYMPLIFY is a multi-centre, observational study with prospective collection and retrospective analysis of blood samples to evaluate the performance of a multi-cancer early detection test within the NHS in England and Wales. The study enrolled almost 6,000 participants between July and November 2021. Recruitment has now completed on 30 November 2021 with a total of 6,240 participants . Individuals consented are over the age of 18 years, willing and able to give informed consent for participation in the study, and referred to a Rapid Diagnostic Centre for non-specific cancer symptoms or a gynaecological, lung, upper gastrointestinal, or lower gastrointestinal urgent “2-week-wait” (2WW) cancer referral pathway. Participants were consented voluntarily and participants could choose to withdraw their consent at any point during the study.

The Primary objective of the study is to evaluate the performance of a GRAIL’s Galleri® MCED test for the detection of invasive cancer.

The Secondary objectives of the study are to evaluate the:

- Performance and yield of the MCED test by referral pathway(i.e. lung, upper Gastrointestinal (GI), lower GI, gynae, and Rapid Diagnostic Centres (RDC)) and cancer type and stage;

- performance of the MCED test for the identification of cancer signal origin (CSO) by referral pathway.

The Exploratory objectives of the study are to:

- evaluate the completeness of patient data collected from central databases locally within 3 months and by 9 months of enrolment, and centrally monthly from 3 through 12 months post enrolment

- estimate if clinical parameters further optimise the performance of MCED test, resource utilisation, the time to diagnostic resolution. and yield of non-cancer diagnoses by referral pathway at 12 months post enrolment

Following informed consent, participants were registered and assigned a study participant identification number. Approximately 40 mL of whole peripheral blood has been collected from all participants. The blood samples collected from participants have been shipped to a laboratory in the UK for processing to plasma and storage. As an observational study, all medical decision making occurred according to established clinical practice in the relevant clinical pathway. There were no protocol-required diagnostic procedures. The result of any diagnostic procedure(s) will be recorded until the date of diagnostic resolution, with patient level data collected from both participating hospital records and NHS datasets.

Clinical information and demographic data will be collected from all participants via case report forms and NHS data sets.

Follow-up data will be collected at each NHS site within 3 months of enrolment to identify cancer diagnoses and serious disease outcomes, and at a later single time point between 6 and 9 months of enrolment for those without diagnostic resolution at 3 months. Rapid cancer registrations data will be requested for monthly transfer from NCRAS from 3 months through to 11 months of follow-up. At each monthly time-point the data will be locked and stored in separate eCRF. This will allow comparison of the centrally collected monthly rapid cancer registrations data with NHS site collected data.

Full cancer registrations data will be collected at 12 months of follow-up and later at a timepoint when full cancer registrations data is available for the 12 months of follow-up. Patient level electronic health records data collected from primary and secondary will also be requested for the 12 month timepoints to capture cancers diagnosed later and healthcare utilisation following recruitment.

The Trial Management Group (TMG) will be responsible for day to day conduct of the study. The TMG consists of the Chief (Chair) and Lead Investigators, Trials Unit representatives, a University of Oxford representative and representatives from GRAIL. The study will be overseen by the relevant oversight committees of the two trials units involved, taking into account input from the GRAIL Clinical Advisory Group.

GRAIL’s Galleri®(Trademarked) MCED test

A new Multi-Cancer Early Detection (MCED) test has been developed that can detect many types of cancer from a single blood sample. This test is called Galleri®™ and this trial aims to find out whether it is better at discovering cancer early, compared to other tests that the NHS currently uses. GRAIL's Galleri®™ MCED blood test is a qualitative, next-generation sequencing (NGS)-based screening test using cell-free DNA isolated from adult human peripheral whole blood. When a cancer signal is detected, the test can also localise the cancer signal with high accuracy. The test report describes one or two Cancer Signal Origins (CSOs). If the first CSO score is high (≥9.0), then only one CSOs is reported, otherwise the two top CSOs are reported. MCED has 21 possible CSOs: anus; bladder; urothelial tract; bone and soft tissue; breast; cervix; colon, rectum; head and neck; kidney; liver/bile duct; lung; lymphoid lineage; melanocytic lineage; myeloid lineage; neuroendocrine; ovary; pancreas, gallbladder; plasma cell lineage; prostate; stomach, oesophagus; thyroid gland; uterus. It is designed as a screening test and not to confirm a cancer diagnosis. Although the test result of "cancer signal detected" with Cancer Signal Origin may indicate the presence of cancer, further investigations to diagnose cancer are necessary in accordance with professional guidelines. As the test requires clinical validation, no individual results will be returned to the study participants or the clinicians responsible for their care.

Patient and Public Involvement and Engagement (PPI&E)

Ongoing PPI&E is conducted throughout the trial. Historical PPI&E was conducted to develop the participant facing materials and on questionnaires, and including specific questions to PPI groups around the sharing of pseudonymised data with GRAIL, LLC. Ongoing PPI&E includes, for example, PPI&E on new participant facing materials, survey feedback on the participant experience, and questionnaires for follow-up of participants.

In the setting up of the trial, GRAIL has taken seriously, strategies for equity of access and has several plans underway to ensure that under-represented minorities are actively recruited into the trial. Amongst this is the invitation strategy, that will identify and actively send invitations to a greater proportion of individuals from these minorities to take part in the trial. It is hoped that this will positively contribute towards equity of access and inform the provision of cancer services in these areas in the future.

DATA SETS REQUESTED:

> Rapid Registrations Cancer Data Set

> Cancer Registry

> Hospital Episode Statistics (HES) Admitted Patient Care (APC)

> Emergency Care Data Set (ECDS)

> HES Outpatients (OP)

> Cancer Waiting Times (Referral data for patients not diagnosed (and therefore not treated)) (CWT)

> Diagnostic Imaging Dataset (DIDS)

************** CHANGES FROM OCTOBER 2022 (Version 2 of this agreement) **************

> HES Admitted Patient Care (APC) - NO CHANGE

> HES Outpatients (OP) - NO CHANGE

> Emergency Care Dataset (ECDS) - To be released on a monthly basis as planned.

> Diagnostic Imaging Dataset (DIDS) - Released from August 2022 on monthly basis as planned.

> Rapid Cancer Registrations Dataset - To be released on a monthly basis as planned. The study team are requesting the addition of date and cause of death code information for whole cohort. This is required for analysis of key secondary endpoints in the study. Date of death was already requested and disseminated under the Cancer registration data and is now requested under Rapid Cancer Registrations additionally. These additional fields in the Rapid Cancer Registrations do not change the scope or the purpose of the original agreement, they are just a request for an additional flow of data. Death data will also be used for reporting subject disposition in the analysis.

> Cancer Waiting Times (CWT) - The study team are requesting to add an additional Cancer Waiting Times referrals from CWT "treatment" table in addition to those from "urgent referrals" table. This change is required to undertake Health Economic Analysis. No change to dissemination frequency.

> Cancer Registration Data - To release NCRD ("gold standard") data on a monthly basis. To expand historic gold standard registration field selection for 1995-2021 and addition of field to allow the trial team to distinguish provisional from finalised gold standard tumours. These changes are required for primary and secondary analysis. Data will be used to characterise the cohort for risk factors (prior cancers), and also assess test performance in a subpopulation of cancer survivors. The Status of Registration is required to enable accurate reporting and filtering of provisional data vs finalised data to internal and external stakeholders, and the interim analysis in the study.

Recruitment for SYMPLIFY occurred between July 2021 to end November 2021. The study team wish to obtain data on participants up to 12 months after last recruitment date, which means the SYMPLIFY team will receive data for the period of July 2021 to November 2022. Due to the delay in the availability of the final data within the Rapid Cancer registrations and Cancer registration datasets, the study team may not receive their final data drop until around November 2023, however this will only contain data for participants up to November 2022 as per participant consent materials.

**************

JUSTIFICATION FOR DATA SETS REQUESTED AND DATA MINIMISATION

All datasets being requested below are for the SYMPLIFY study enrolled population only. Additionally, only the data fields deemed to be important for analyses have been requested. Provision of data will be limited to the period from Date of Consent up to 12 months after this date.

> Cancer Registry and Rapid Registrations - These central NHS datasets will be the sole source for the data required for primary and secondary (exploratory) objectives analyses in the Study. They will be used to identify Primary endpoints, which are:

1. To evaluate the performance of a MCED test for the detection of invasive cancer and the identification of cancer signal origin (CSO).

2. To evaluate the performance of a MCED test by referral pathway (i.e. lung, upper Gastrointestinal (GI), lower GI, gynae, and Rapid Diagnostic Centres (RDC)) and cancer type and stage.

3. To compare the Common Scientific Outline (CSO) predicted by the patient’s GP versus that predicted by MCED.

4. To evaluate the yield with MCED by referral pathway by the number of true positives/number of patients referred within each referral pathway.

5. To evaluate the completeness of patient data collected from central databases by looking at the proportion of completed data fields, according to locally and centrally sourced inputs.

6. To investigate if clinical parameters further optimise the performance of MCED test

7. To evaluate the time to diagnostic resolution by referral pathway.

> Hospital Episode Statistics (HES) Outpatients (OP), Admitted Patient Care (APC) and Emergency Care Data Set (ECDS), Cancer Waiting Times (Referrals) (CWT) and Diagnostic Imaging Dataset (DIDS) - Will be used to identify Secondary endpoints:

1. To estimate resource utilisation by referral pathway by the number of encounters, tests, and referrals required to achieve diagnostic resolution

2. To evaluate the yield of non-cancer diagnoses following referral by the number of patients diagnosed with non-cancer/number of patients referred.

The SYMPLIFY study is funded by an unrestricted educational grant from GRAIL Bio UK Ltd and supported by NHS England, NHS Wales, the National Institute for Health Research (NIHR) and the Oxford NIHR Biomedical Research Centre. NHS England, NHS Wales and the NIHR will not have access to record-level NHS Digital data, and they do not in any way decide the purpose of the study, how it is run, or the means of data processing, nor have any access to record-level NHS Digital data. NHS Digital therefore do not consider them to be a Data Controllers.

GDPR Legal Basis for the Processing of Personal Data:

University of Oxford, as joint Data Controller (and Lead), are using Article 6:1(e): Specific task in the ‘public interest’ or task that has a clear basis in law.

GRAIL Bio UK Ltd, as a joint Data Controller, are using Article 6(1)(f) "processing is necessary for the purposes of the legitimate interests pursued by the controller or by a third party except where such interests are overridden by the interests or fundamental rights and freedoms of the data subject which require protection of personal data, in particular where the data subject is a child." Processing personal data is necessary for GRAIL Bio UK Ltd’s legitimate interests which are described in this application. The data to which access is requested are proportionate and necessary to achieve those interests. GRAIL Bio UK Ltd have completed a legitimate interests assessment (LIA) and are satisfied that the interests of the data subjects do not override their legitimate interests; that they would reasonably expect the processing and it would not cause unjustified harm. The data subjects interests and fundamental rights are protected through appropriate minimisation of fields and patient records being processed; protection of the data in a secure environment, and guaranteeing secure destruction at any stage at the request of NHS Digital or after a defined period on completion of the project. NHS Digital have compared this LIA against the ICO’s checklist (https://ico.org.uk/for-organisations/guide-to-the-general-data-protection-regulation-gdpr/lawful-basis-for-processing/legitimate-interests/) and are content that all requirements are met.

Additionally (as health data is a special category of Personal Data), both University of Oxford and GRAIL Bio UK Ltd are using Article 9:2(j): Special category data used for “Archiving in the public interest, scientific or historical research or statistical purposes”, with a basis in law.

Organisation Roles and Responsibilities:

• University of Oxford is the lead Data Controller. They are responsible for sponsoring the trial and who also process the data and are responsible for data handling. They will also perform all protocol outlined analyses of NHS Digital data, and are therefore also the Data Processor for this agreement

• GRAIL Bio UK Ltd are the joint Data Controller. They are responsible for funding the trial and processing and analysing the blood samples. They will not receive any NHS Digital data outlined in this agreement unless is is aggregated with small number suppression applied as per the HES Analysis guide.

• GRAIL, Limited Liability Company (LLC). are the manufacturers of the MCED test, Galleri®(Trademarked), and has set up the above UK subsidiary, GRAIL Bio UK Ltd. When approval is in place and this agreement has been updated through the NHS Digital assurance process, GRAIL, LLC will be added as a data processor. At that time, GRAIL, LLC will be receiving pseudonymised record-level NHS Digital data from University of Oxford *** Under this version (v2) and version 1 of this agreement, the pseudonymised record-level data will not yet be transferred outside of the UK. ***

In the future, GRAIL Bio UK Ltd may receive commercial benefit (including intangible or indirect commercial benefits such as positive publicity) from the successful outcomes of the trial. GRAIL Bio UK Ltd and the NHS have entered into a partnership whereby the Galleri®™ test will be piloted in clinical trials within the NHS in England. If the test is shown to work as intended in these clinical trials, the NHS may purchase the test from GRAIL and make the test routinely available in the future to benefit patient.

An early interim analysis will be based on data captured within 3 months after enrolment and a late/complete analysis based on data at 12 months after enrolment to account for delayed diagnoses (including the 9-month and 12-month follow-up data). The output from the interim analysis will include a study report summarizing the results of the primary, secondary and first exploratory objective as noted in the Processing Activities section above.

The key exploratory objective for the study is the analysis of the completeness and quality of cancer diagnostic pathway data gathered from central NHS databases as compared to locally collected data. Datapoints collected locally within 3 months and by 9 months of enrolment will be compared to data collected centrally monthly from 3 through 12 months post enrolment. The completeness, by capture method, and concordance between methods of each data field will be summarised descriptively in the clinical study reports at both interim and end of study timepoint. This will inform the potential to use central data capture for future large-scale studies in the field, as well as identify areas for improvement in central data linkage.

The outputs of data processing at the end of the study aim to include conference abstracts, reports to NHS England and GRAIL, and submissions of SYMPLIFY findings to peer reviewed journal(s). The publications will not contain the data, only the results of its statistical analysis that will be summarised overall, by cancer site, referral pathway. Health economic analyses aims to examine the number of encounters to diagnosis; number and types of tests for diagnosis; comparisons of resource utilisation observed to modelled resource utilisation based on cancer signal detected and CSO.

All outputs will be aggregated with small number suppressed as per the HES analysis guide or according to the specific data set's suppression guidance.

GRAIL may take the results of the SYMPLIFY study to further refine the algorithm of their MCED test that could add commercial value to their product(s). Results of SYMPLIFY may also inform decisions to fund future cancer research in the NHS and/or future decisions to procure a GRAIL test for use in the NHS.

TARGET DATES

The interim analysis is due to be completed by the end of Quarter 2 in 2022. The final 12-month analysis is expected to be complete by the end of 2023.

This version (v2 - October 2022) is a minor amendment to the data specification. Yielded benefits are not reportable at this time but will be included in the next major amendment.

The University of Oxford and GRAIL Bio UK Ltd, as joint data controllers, are requesting access to pseudonymised record-level data linked against a cohort of individually consented patients recruited to SYMPLIFY, a study designed to assess GRAIL’s Galleri®(Trademarked) multi-cancer early detection (MCED) test in individuals referred with signs and symptoms of cancer.

Note that all members of the team running the trial are based at the Oncology Clinical Trials Office (OCTO) and Primary Care & Vaccine Collaborative Clinical Trials Unit at University of Oxford (UoO). For the sake of consistency, and as UoO is listed as a data controller, when referring to UoO throughout the application, this encompasses the team at OCTO and Primary Care & Vaccine Collaborative Clinical Trials Unit.

Background, Purpose and Rationale behind SYMPLIFY:

SYMPLIFY is a multi-centre, observational study with prospective collection and retrospective analysis of blood samples to evaluate the performance of a multi-cancer early detection test within the NHS in England and Wales. The study enrolled almost 6,000 participants between July and November 2021. Recruitment has now completed on 30 November 2021 with a total of 6,240 participants . Individuals consented are over the age of 18 years, willing and able to give informed consent for participation in the study, and referred to a Rapid Diagnostic Centre for non-specific cancer symptoms or a gynaecological, lung, upper gastrointestinal, or lower gastrointestinal urgent “2-week-wait” (2WW) cancer referral pathway. Participants were consented voluntarily and participants could choose to withdraw their consent at any point during the study.

The Primary objective of the study is to evaluate the performance of a GRAIL’s Galleri® MCED test for the detection of invasive cancer.

The Secondary objectives of the study are to evaluate the:

- Performance and yield of the MCED test by referral pathway(i.e. lung, upper Gastrointestinal (GI), lower GI, gynae, and Rapid Diagnostic Centres (RDC)) and cancer type and stage;

- performance of the MCED test for the identification of cancer signal origin (CSO) by referral pathway.

The Exploratory objectives of the study are to:

- evaluate the completeness of patient data collected from central databases locally within 3 months and by 9 months of enrolment, and centrally monthly from 3 through 12 months post enrolment

- estimate if clinical parameters further optimise the performance of MCED test, resource utilisation, the time to diagnostic resolution. and yield of non-cancer diagnoses by referral pathway at 12 months post enrolment

Following informed consent, participants were registered and assigned a study participant identification number. Approximately 40 mL of whole peripheral blood has been collected from all participants. The blood samples collected from participants have been shipped to a laboratory in the UK for processing to plasma and storage. As an observational study, all medical decision making occurred according to established clinical practice in the relevant clinical pathway. There were no protocol-required diagnostic procedures. The result of any diagnostic procedure(s) will be recorded until the date of diagnostic resolution, with patient level data collected from both participating hospital records and NHS datasets.

Clinical information and demographic data will be collected from all participants via case report forms and NHS data sets.

Follow-up data will be collected at each NHS site within 3 months of enrolment to identify cancer diagnoses and serious disease outcomes, and at a later single time point between 6 and 9 months of enrolment for those without diagnostic resolution at 3 months. Rapid cancer registrations data will be requested for monthly transfer from NCRAS from 3 months through to 11 months of follow-up. At each monthly time-point the data will be locked and stored in separate eCRF. This will allow comparison of the centrally collected monthly rapid cancer registrations data with NHS site collected data.

Full cancer registrations data will be collected at 12 months of follow-up and later at a timepoint when full cancer registrations data is available for the 12 months of follow-up. Patient level electronic health records data collected from primary and secondary will also be requested for the 12 month timepoints to capture cancers diagnosed later and healthcare utilisation following recruitment.

The Trial Management Group (TMG) will be responsible for day to day conduct of the study. The TMG consists of the Chief (Chair) and Lead Investigators, Trials Unit representatives, a University of Oxford representative and representatives from GRAIL. The study will be overseen by the relevant oversight committees of the two trials units involved, taking into account input from the GRAIL Clinical Advisory Group.

GRAIL’s Galleri®(Trademarked) MCED test

A new Multi-Cancer Early Detection (MCED) test has been developed that can detect many types of cancer from a single blood sample. This test is called Galleri®™ and this trial aims to find out whether it is better at discovering cancer early, compared to other tests that the NHS currently uses. GRAIL's Galleri®™ MCED blood test is a qualitative, next-generation sequencing (NGS)-based screening test using cell-free DNA isolated from adult human peripheral whole blood. When a cancer signal is detected, the test can also localise the cancer signal with high accuracy. The test report describes one or two Cancer Signal Origins (CSOs). If the first CSO score is high (≥9.0), then only one CSOs is reported, otherwise the two top CSOs are reported. MCED has 21 possible CSOs: anus; bladder; urothelial tract; bone and soft tissue; breast; cervix; colon, rectum; head and neck; kidney; liver/bile duct; lung; lymphoid lineage; melanocytic lineage; myeloid lineage; neuroendocrine; ovary; pancreas, gallbladder; plasma cell lineage; prostate; stomach, oesophagus; thyroid gland; uterus. It is designed as a screening test and not to confirm a cancer diagnosis. Although the test result of "cancer signal detected" with Cancer Signal Origin may indicate the presence of cancer, further investigations to diagnose cancer are necessary in accordance with professional guidelines. As the test requires clinical validation, no individual results will be returned to the study participants or the clinicians responsible for their care.

Patient and Public Involvement and Engagement (PPI&E)

Ongoing PPI&E is conducted throughout the trial. Historical PPI&E was conducted to develop the participant facing materials and on questionnaires, and including specific questions to PPI groups around the sharing of pseudonymised data with GRAIL, LLC. Ongoing PPI&E includes, for example, PPI&E on new participant facing materials, survey feedback on the participant experience, and questionnaires for follow-up of participants.

In the setting up of the trial, GRAIL has taken seriously, strategies for equity of access and has several plans underway to ensure that under-represented minorities are actively recruited into the trial. Amongst this is the invitation strategy, that will identify and actively send invitations to a greater proportion of individuals from these minorities to take part in the trial. It is hoped that this will positively contribute towards equity of access and inform the provision of cancer services in these areas in the future.

DATA SETS REQUESTED:

> Rapid Registrations Cancer Data Set

> Cancer Registry

> Hospital Episode Statistics (HES) Admitted Patient Care (APC)

> Emergency Care Data Set (ECDS)

> HES Outpatients (OP)

> Cancer Waiting Times (Referral data for patients not diagnosed (and therefore not treated)) (CWT)

> Diagnostic Imaging Dataset (DIDS)

JUSTIFICATION FOR DATA SETS REQUESTED AND DATA MINIMISATION

All datasets being requested below are for the SYMPLIFY study enrolled population only. Additionally, only the data fields deemed to be important for analyses have been requested. Provision of data will be limited to the period from Date of Consent up to 12 months after this date.

> Cancer Registry and Rapid Registrations - These central NHS datasets will be the sole source for the data required for primary and secondary (exploratory) objectives analyses in the Study. They will be used to identify Primary endpoints, which are:

1. To evaluate the performance of a MCED test for the detection of invasive cancer and the identification of cancer signal origin (CSO).

2. To evaluate the performance of a MCED test by referral pathway (i.e. lung, upper Gastrointestinal (GI), lower GI, gynae, and Rapid Diagnostic Centres (RDC)) and cancer type and stage.

3. To compare the Common Scientific Outline (CSO) predicted by the patient’s GP versus that predicted by MCED.

4. To evaluate the yield with MCED by referral pathway by the number of true positives/number of patients referred within each referral pathway.

5. To evaluate the completeness of patient data collected from central databases by looking at the proportion of completed data fields, according to locally and centrally sourced inputs.

6. To investigate if clinical parameters further optimise the performance of MCED test

7. To evaluate the time to diagnostic resolution by referral pathway.

> Hospital Episode Statistics (HES) Outpatients (OP), Admitted Patient Care (APC) and Emergency Care Data Set (ECDS), Cancer Waiting Times (Referrals) (CWT) and Diagnostic Imaging Dataset (DIDS) - Will be used to identify Secondary endpoints:

1. To estimate resource utilisation by referral pathway by the number of encounters, tests, and referrals required to achieve diagnostic resolution

2. To evaluate the yield of non-cancer diagnoses following referral by the number of patients diagnosed with non-cancer/number of patients referred.

The SYMPLIFY study is funded by an unrestricted educational grant from GRAIL Bio UK Ltd and supported by NHS England, NHS Wales, the National Institute for Health Research (NIHR) and the Oxford NIHR Biomedical Research Centre. NHS England, NHS Wales and the NIHR will not have access to record-level NHS Digital data, and they do not in any way decide the purpose of the study, how it is run, or the means of data processing, nor have any access to record-level NHS Digital data. NHS Digital therefore do not consider them to be a Data Controllers.

GDPR Legal Basis for the Processing of Personal Data:

University of Oxford, as joint Data Controller (and Lead), are using Article 6:1(e): Specific task in the ‘public interest’ or task that has a clear basis in law.

GRAIL Bio UK Ltd, as a joint Data Controller, are using Article 6(1)(f) "processing is necessary for the purposes of the legitimate interests pursued by the controller or by a third party except where such interests are overridden by the interests or fundamental rights and freedoms of the data subject which require protection of personal data, in particular where the data subject is a child." Processing personal data is necessary for GRAIL Bio UK Ltd’s legitimate interests which are described in this application. The data to which access is requested are proportionate and necessary to achieve those interests. GRAIL Bio UK Ltd have completed a legitimate interests assessment (LIA) and are satisfied that the interests of the data subjects do not override their legitimate interests; that they would reasonably expect the processing and it would not cause unjustified harm. The data subjects interests and fundamental rights are protected through appropriate minimisation of fields and patient records being processed; protection of the data in a secure environment, and guaranteeing secure destruction at any stage at the request of NHS Digital or after a defined period on completion of the project. NHS Digital have compared this LIA against the ICO’s checklist (https://ico.org.uk/for-organisations/guide-to-the-general-data-protection-regulation-gdpr/lawful-basis-for-processing/legitimate-interests/) and are content that all requirements are met.

Additionally (as health data is a special category of Personal Data), both University of Oxford and GRAIL Bio UK Ltd are using Article 9:2(j): Special category data used for “Archiving in the public interest, scientific or historical research or statistical purposes”, with a basis in law.

Organisation Roles and Responsibilities:

• University of Oxford is the lead Data Controller. They are responsible for sponsoring the trial and who also process the data and are responsible for data handling. They will also perform all protocol outlined analyses of NHS Digital data, and are therefore also the Data Processor for this agreement

• GRAIL Bio UK Ltd are the joint Data Controller. They are responsible for funding the trial and processing and analysing the blood samples. They will not receive any NHS Digital data outlined in this agreement unless is is aggregated with small number suppression applied as per the HES Analysis guide.

• GRAIL, Limited Liability Company (LLC). are the manufacturers of the MCED test, Galleri®(Trademarked), and has set up the above UK subsidiary, GRAIL Bio UK Ltd. GRAIL, LLC will be receiving pseudonymised record-level NHS Digital data from University of Oxford, and are therefore listed as a Data Processor in this agreement.

In the future, GRAIL Bio UK Ltd may receive commercial benefit (including intangible or indirect commercial benefits such as positive publicity) from the successful outcomes of the trial. GRAIL Bio UK Ltd and the NHS have entered into a partnership whereby the Galleri®™ test will be piloted in clinical trials within the NHS in England. If the test is shown to work as intended in these clinical trials, the NHS may purchase the test from GRAIL and make the test routinely available in the future to benefit patient.

An early interim analysis will be based on data captured within 3 months after enrolment and a late/complete analysis based on data at 12 months after enrolment to account for delayed diagnoses (including the 9-month and 12-month follow-up data). The output from the interim analysis will include a study report summarizing the results of the primary, secondary and first exploratory objective as noted in the Processing Activities section above.

The key exploratory objective for the study is the analysis of the completeness and quality of cancer diagnostic pathway data gathered from central NHS databases as compared to locally collected data. Datapoints collected locally within 3 months and by 9 months of enrolment will be compared to data collected centrally monthly from 3 through 12 months post enrolment. The completeness, by capture method, and concordance between methods of each data field will be summarized descriptively in the clinical study reports at both interim and end of study timepoint. This will inform the potential to use central data capture for future large-scale studies in the field, as well as identify areas for improvement in central data linkage.

The outputs of data processing at the end of the study aim to include conference abstracts, reports to NHS England and GRAIL, and submissions of SYMPLIFY findings to peer reviewed journal(s). The publications will not contain the data, only the results of its statistical analysis that will be summarized overall, by cancer site, referral pathway. Health economic analyses aims to examine the number of encounters to diagnosis; number and types of tests for diagnosis; comparisons of resource utilisation observed to modelled resource utilisation based on cancer signal detected and CSO.

All outputs will be aggregated with small number suppressed as per the HES analysis guide or according to the specific data set's suppression guidance.

GRAIL may take the results of the SYMPLIFY study to further refine the algorithm of their MCED test that could add commercial value to their product(s). Results of SYMPLIFY may also inform decisions to fund future cancer research in the NHS and/or future decisions to procure a GRAIL test for use in the NHS.

TARGET DATES

The interim analysis is due to be completed by the end of Quarter 2 in 2022. The final 12-month analysis is expected to be complete by the end of 2023.

The University of Oxford and GRAIL Bio UK Ltd, as joint data controllers, are requesting access to pseudonymised record-level data linked against a cohort of individually consented patients recruited to SYMPLIFY, a study designed to assess GRAIL’s Galleri®(Trademarked) multi-cancer early detection (MCED) test in individuals referred with signs and symptoms of cancer.

Note that all members of the team running the trial are based at the Oncology Clinical Trials Office (OCTO) and Primary Care & Vaccine Collaborative Clinical Trials Unit at University of Oxford (UoO). For the sake of consistency, and as UoO is listed as a data controller, when referring to UoO throughout the application, this encompasses the team at OCTO and Primary Care & Vaccine Collaborative Clinical Trials Unit.

Background, Purpose and Rationale behind SYMPLIFY:

SYMPLIFY is a multi-centre, observational study with prospective collection and retrospective analysis of blood samples to evaluate the performance of a multi-cancer early detection test within the NHS in England and Wales. The study enrolled almost 6,000 participants between July and November 2021. Recruitment has now completed on 30 November 2021 with a total of 6,240 participants . Individuals consented are over the age of 18 years, willing and able to give informed consent for participation in the study, and referred to a Rapid Diagnostic Centre for non-specific cancer symptoms or a gynaecological, lung, upper gastrointestinal, or lower gastrointestinal urgent “2-week-wait” (2WW) cancer referral pathway. Participants were consented voluntarily and participants could choose to withdraw their consent at any point during the study.

The Primary objective of the study is to evaluate the performance of a GRAIL’s Galleri® MCED test for the detection of invasive cancer.

The Secondary objectives of the study are to evaluate the:

- Performance and yield of the MCED test by referral pathway(i.e. lung, upper Gastrointestinal (GI), lower GI, gynae, and Rapid Diagnostic Centres (RDC)) and cancer type and stage;

- performance of the MCED test for the identification of cancer signal origin (CSO) by referral pathway.

The Exploratory objectives of the study are to:

- evaluate the completeness of patient data collected from central databases locally within 3 months and by 9 months of enrolment, and centrally monthly from 3 through 12 months post enrolment

- estimate if clinical parameters further optimise the performance of MCED test, resource utilisation, the time to diagnostic resolution. and yield of non-cancer diagnoses by referral pathway at 12 months post enrolment

Following informed consent, participants were registered and assigned a study participant identification number. Approximately 40 mL of whole peripheral blood has been collected from all participants. The blood samples collected from participants have been shipped to a laboratory in the UK for processing to plasma and storage. As an observational study, all medical decision making occurred according to established clinical practice in the relevant clinical pathway. There were no protocol-required diagnostic procedures. The result of any diagnostic procedure(s) will be recorded until the date of diagnostic resolution, with patient level data collected from both participating hospital records and NHS datasets.

Clinical information and demographic data will be collected from all participants via case report forms and NHS data sets.

Follow-up data will be collected at each NHS site within 3 months of enrolment to identify cancer diagnoses and serious disease outcomes, and at a later single time point between 6 and 9 months of enrolment for those without diagnostic resolution at 3 months. Rapid cancer registrations data will be requested for monthly transfer from NCRAS from 3 months through to 11 months of follow-up. At each monthly time-point the data will be locked and stored in separate eCRF. This will allow comparison of the centrally collected monthly rapid cancer registrations data with NHS site collected data.

Full cancer registrations data will be collected at 12 months of follow-up and later at a timepoint when full cancer registrations data is available for the 12 months of follow-up. Patient level electronic health records data collected from primary and secondary will also be requested for the 12 month timepoints to capture cancers diagnosed later and healthcare utilisation following recruitment.

The Trial Management Group (TMG) will be responsible for day to day conduct of the study. The TMG consists of the Chief (Chair) and Lead Investigators, Trials Unit representatives, a University of Oxford representative and representatives from GRAIL. The study will be overseen by the relevant oversight committees of the two trials units involved, taking into account input from the GRAIL Clinical Advisory Group.

GRAIL’s Galleri®(Trademarked) MCED test

A new Multi-Cancer Early Detection (MCED) test has been developed that can detect many types of cancer from a single blood sample. This test is called Galleri®™ and this trial aims to find out whether it is better at discovering cancer early, compared to other tests that the NHS currently uses. GRAIL's Galleri®™ MCED blood test is a qualitative, next-generation sequencing (NGS)-based screening test using cell-free DNA isolated from adult human peripheral whole blood. When a cancer signal is detected, the test can also localise the cancer signal with high accuracy. The test report describes one or two Cancer Signal Origins (CSOs). If the first CSO score is high (≥9.0), then only one CSOs is reported, otherwise the two top CSOs are reported. MCED has 21 possible CSOs: anus; bladder; urothelial tract; bone and soft tissue; breast; cervix; colon, rectum; head and neck; kidney; liver/bile duct; lung; lymphoid lineage; melanocytic lineage; myeloid lineage; neuroendocrine; ovary; pancreas, gallbladder; plasma cell lineage; prostate; stomach, oesophagus; thyroid gland; uterus. It is designed as a screening test and not to confirm a cancer diagnosis. Although the test result of "cancer signal detected" with Cancer Signal Origin may indicate the presence of cancer, further investigations to diagnose cancer are necessary in accordance with professional guidelines. As the test requires clinical validation, no individual results will be returned to the study participants or the clinicians responsible for their care.

Patient and Public Involvement and Engagement (PPI&E)

Ongoing PPI&E is conducted throughout the trial. Historical PPI&E was conducted to develop the participant facing materials and on questionnaires, and including specific questions to PPI groups around the sharing of pseudonymised data with GRAIL, LLC. Ongoing PPI&E includes, for example, PPI&E on new participant facing materials, survey feedback on the participant experience, and questionnaires for follow-up of participants.

In the setting up of the trial, GRAIL has taken seriously, strategies for equity of access and has several plans underway to ensure that under-represented minorities are actively recruited into the trial. Amongst this is the invitation strategy, that will identify and actively send invitations to a greater proportion of individuals from these minorities to take part in the trial. It is hoped that this will positively contribute towards equity of access and inform the provision of cancer services in these areas in the future.

DATA SETS REQUESTED:

> Rapid Registrations Cancer Data Set

> Cancer Registry

> Hospital Episode Statistics (HES) Admitted Patient Care (APC)

> Emergency Care Data Set (ECDS)

> HES Outpatients (OP)

> Cancer Waiting Times (Referral data for patients not diagnosed (and therefore not treated)) (CWT)

> Diagnostic Imaging Dataset (DIDS)

JUSTIFICATION FOR DATA SETS REQUESTED AND DATA MINIMISATION

All datasets being requested below are for the SYMPLIFY study enrolled population only. Additionally, only the data fields deemed to be important for analyses have been requested. Provision of data will be limited to the period from Date of Consent up to 12 months after this date.

> Cancer Registry and Rapid Registrations - These central NHS datasets will be the sole source for the data required for primary and secondary (exploratory) objectives analyses in the Study. They will be used to identify Primary endpoints, which are:

1. To evaluate the performance of a MCED test for the detection of invasive cancer and the identification of cancer signal origin (CSO).

2. To evaluate the performance of a MCED test by referral pathway (i.e. lung, upper Gastrointestinal (GI), lower GI, gynae, and Rapid Diagnostic Centres (RDC)) and cancer type and stage.

3. To compare the Common Scientific Outline (CSO) predicted by the patient’s GP versus that predicted by MCED.

4. To evaluate the yield with MCED by referral pathway by the number of true positives/number of patients referred within each referral pathway.

5. To evaluate the completeness of patient data collected from central databases by looking at the proportion of completed data fields, according to locally and centrally sourced inputs.

6. To investigate if clinical parameters further optimise the performance of MCED test

7. To evaluate the time to diagnostic resolution by referral pathway.

> Hospital Episode Statistics (HES) Outpatients (OP), Admitted Patient Care (APC) and Emergency Care Data Set (ECDS), Cancer Waiting Times (Referrals) (CWT) and Diagnostic Imaging Dataset (DIDS) - Will be used to identify Secondary endpoints:

1. To estimate resource utilisation by referral pathway by the number of encounters, tests, and referrals required to achieve diagnostic resolution

2. To evaluate the yield of non-cancer diagnoses following referral by the number of patients diagnosed with non-cancer/number of patients referred.

The SYMPLIFY study is funded by an unrestricted educational grant from GRAIL Bio UK Ltd and supported by NHS England, NHS Wales, the National Institute for Health Research (NIHR) and the Oxford NIHR Biomedical Research Centre. NHS England, NHS Wales and the NIHR will not have access to record-level NHS Digital data, and they do not in any way decide the purpose of the study, how it is run, or the means of data processing, nor have any access to record-level NHS Digital data. NHS Digital therefore do not consider them to be a Data Controllers.

GDPR Legal Basis for the Processing of Personal Data:

University of Oxford, as joint Data Controller (and Lead), are using Article 6:1(e): Specific task in the ‘public interest’ or task that has a clear basis in law.

GRAIL Bio UK Ltd, as a joint Data Controller, are using Article 6(1)(f) "processing is necessary for the purposes of the legitimate interests pursued by the controller or by a third party except where such interests are overridden by the interests or fundamental rights and freedoms of the data subject which require protection of personal data, in particular where the data subject is a child." Processing personal data is necessary for GRAIL Bio UK Ltd’s legitimate interests which are described in this application. The data to which access is requested are proportionate and necessary to achieve those interests. GRAIL Bio UK Ltd have completed a legitimate interests assessment (LIA) and are satisfied that the interests of the data subjects do not override their legitimate interests; that they would reasonably expect the processing and it would not cause unjustified harm. The data subjects interests and fundamental rights are protected through appropriate minimisation of fields and patient records being processed; protection of the data in a secure environment, and guaranteeing secure destruction at any stage at the request of NHS Digital or after a defined period on completion of the project. NHS Digital have compared this LIA against the ICO’s checklist (https://ico.org.uk/for-organisations/guide-to-the-general-data-protection-regulation-gdpr/lawful-basis-for-processing/legitimate-interests/) and are content that all requirements are met.

Additionally (as health data is a special category of Personal Data), both University of Oxford and GRAIL Bio UK Ltd are using Article 9:2(j): Special category data used for “Archiving in the public interest, scientific or historical research or statistical purposes”, with a basis in law.

Organisation Roles and Responsibilities:

• University of Oxford is the lead Data Controller. They are responsible for sponsoring the trial and who also process the data and are responsible for data handling. They will also perform all protocol outlined analyses of NHS Digital data, and are therefore also the Data Processor for this agreement

• GRAIL Bio UK Ltd are the joint Data Controller. They are responsible for funding the trial and processing and analysing the blood samples. They will not receive any NHS Digital data outlined in this agreement unless is is aggregated with small number suppression applied as per the HES Analysis guide.

• GRAIL, Limited Liability Company (LLC). are the manufacturers of the MCED test, Galleri®(Trademarked), and has set up the above UK subsidiary, GRAIL Bio UK Ltd. GRAIL, LLC will be receiving pseudonymised record-level NHS Digital data from University of Oxford, and are therefore listed as a Data Processor in this agreement.

In the future, GRAIL Bio UK Ltd may receive commercial benefit (including intangible or indirect commercial benefits such as positive publicity) from the successful outcomes of the trial. GRAIL Bio UK Ltd and the NHS have entered into a partnership whereby the Galleri®™ test will be piloted in clinical trials within the NHS in England. If the test is shown to work as intended in these clinical trials, the NHS may purchase the test from GRAIL and make the test routinely available in the future to benefit patient.

An early interim analysis will be based on data captured within 3 months after enrolment and a late/complete analysis based on data at 12 months after enrolment to account for delayed diagnoses (including the 9-month and 12-month follow-up data). The output from the interim analysis will include a study report summarizing the results of the primary, secondary and first exploratory objective as noted in the Processing Activities section above.

The key exploratory objective for the study is the analysis of the completeness and quality of cancer diagnostic pathway data gathered from central NHS databases as compared to locally collected data. Datapoints collected locally within 3 months and by 9 months of enrolment will be compared to data collected centrally monthly from 3 through 12 months post enrolment. The completeness, by capture method, and concordance between methods of each data field will be summarized descriptively in the clinical study reports at both interim and end of study timepoint. This will inform the potential to use central data capture for future large-scale studies in the field, as well as identify areas for improvement in central data linkage.

The outputs of data processing at the end of the study aim to include conference abstracts, reports to NHS England and GRAIL, and submissions of SYMPLIFY findings to peer reviewed journal(s). The publications will not contain the data, only the results of its statistical analysis that will be summarized overall, by cancer site, referral pathway. Health economic analyses aims to examine the number of encounters to diagnosis; number and types of tests for diagnosis; comparisons of resource utilisation observed to modelled resource utilisation based on cancer signal detected and CSO.

All outputs will be aggregated with small number suppressed as per the HES analysis guide or according to the specific data set's suppression guidance.

GRAIL may take the results of the SYMPLIFY study to further refine the algorithm of their MCED test that could add commercial value to their product(s). Results of SYMPLIFY may also inform decisions to fund future cancer research in the NHS and/or future decisions to procure a GRAIL test for use in the NHS.

TARGET DATES

The interim analysis is due to be completed by the end of Quarter 2 in 2022. The final 12-month analysis is expected to be complete by the end of 2023.

Yielded Benefits is not a requirement for new applications.